Genetic Variant OCLN:p.Val308Leu (chr5-69534724-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001205254.2(OCLN):c.922G>C(p.Val308Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 7 hom., cov: 11)

Exomes 𝑓: 0.0015 ( 58 hom. )

Consequence

OCLN
NM_001205254.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.87

Variant links:

Genes affected

OCLN (HGNC:8104): (occludin) This gene encodes an integral membrane protein that is required for cytokine-induced regulation of the tight junction paracellular permeability barrier. Mutations in this gene are thought to be a cause of band-like calcification with simplified gyration and polymicrogyria (BLC-PMG), an autosomal recessive neurologic disorder that is also known as pseudo-TORCH syndrome. Alternative splicing results in multiple transcript variants. A related pseudogene is present 1.5 Mb downstream on the q arm of chromosome 5. [provided by RefSeq, Apr 2011]

OCLN links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020353496).

BP6

Variant 5-69534724-G-C is Benign according to our data. Variant chr5-69534724-G-C is described in ClinVar as [Benign]. Clinvar id is 1283292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-69534724-G-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0102 (951/93458) while in subpopulation AFR AF= 0.0456 (884/19400). AF 95% confidence interval is 0.0431. There are 7 homozygotes in gnomad4. There are 437 alleles in male gnomad4 subpopulation. Median coverage is 11. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OCLN	NM_001205254.2 link	c.922G>C	p.Val308Leu	missense_variant	Exon 5 of 9	ENST00000396442.7	NP_001192183.1	Q16625-1A8K3T2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OCLN	ENST00000396442.7 link	c.922G>C	p.Val308Leu	missense_variant	Exon 5 of 9	1	NM_001205254.2	ENSP00000379719.2		Q16625-1

Frequencies

GnomAD3 genomes

AF:

0.0101

AC:

943

AN:

93388

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0453

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00361

Gnomad ASJ

AF:

0.00533

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00373

Gnomad NFE

AF:

0.000183

Gnomad OTH

AF:

0.00955

GnomAD3 exomes

AF:

0.00361

AC:

820

AN:

226864

Hom.:

110

AF XY:

0.00308

AC XY:

381

AN XY:

123502

show subpopulations

Gnomad AFR exome

AF:

0.0539

Gnomad AMR exome

AF:

0.00277

Gnomad ASJ exome

AF:

0.00528

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000179

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000186

Gnomad OTH exome

AF:

0.00216

GnomAD4 exome

AF:

0.00153

AC:

1270

AN:

828788

Hom.:

Cov.:

AF XY:

0.00135

AC XY:

582

AN XY:

431272

show subpopulations

Gnomad4 AFR exome

AF:

0.0491

Gnomad4 AMR exome

AF:

0.00257

Gnomad4 ASJ exome

AF:

0.00391

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000156

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000155

Gnomad4 OTH exome

AF:

0.00329

GnomAD4 genome

AF:

0.0102

AC:

951

AN:

93458

Hom.:

Cov.:

AF XY:

0.0101

AC XY:

437

AN XY:

43328

show subpopulations

Gnomad4 AFR

AF:

0.0456

Gnomad4 AMR

AF:

0.00361

Gnomad4 ASJ

AF:

0.00533

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000184

Gnomad4 OTH

AF:

0.00937

Alfa

AF:

0.00211

Hom.:

ESP6500AA

AF:

0.0522

AC:

177

ESP6500EA

AF:

0.000247

AC:

ExAC

AF:

0.00532

AC:

630

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.68

DEOGEN2

Benign

0.062

T;T;.

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.71

.;T;T

MetaRNN

Benign

0.0020

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.7

L;L;.

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.070

N;N;N

REVEL

Benign

0.14

Sift

Benign

0.90

T;T;T

Sift4G

Benign

0.88

T;T;T

Polyphen

0.0070

B;B;.

Vest4

0.23

MutPred

0.12

Gain of glycosylation at P311 (P = 0.105);Gain of glycosylation at P311 (P = 0.105);.;

MVP

0.59

MPC

1.9

ClinPred

0.0016

GERP RS

1.8

Varity_R

0.040

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over